ANZCTR - Registration

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Trial registered on ANZCTR

Registration number

ACTRN12622001193763p

Ethics application status

Submitted, not yet approved

Date submitted

3/08/2022

Date registered

6/09/2022

Date last updated

6/09/2022

Date data sharing statement initially provided

6/09/2022

Type of registration

Prospectively registered

Titles & IDs

Public title

Phosphate Replacement In Critical Illness: the PRICE-1 trial

Scientific title

The effect of liberal versus restrictive phosphate replacement on total phosphate administration in adult critically ill patients: a Phase-2 cluster, crossover, database-integrated, randomised, controlled trial

Secondary ID [1]

Nil Known

Universal Trial Number (UTN)

U1111-1279-4796

Trial acronym

PRICE-1

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Derangement of serum phosphate concentrations

Condition category

Condition code

Metabolic and Endocrine

Other metabolic disorders

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

Three ICUs will be randomised to use either the restrictive or liberal phosphate replacement protocol for a three-month period, followed by a one-month washout period. The sites will then crossover to the alternate phosphate replacement protocol for another three-month period.

For the duration of the trial, all patients admitted to participating ICUs will have phosphate replacement delivered as per the study-allocated phosphate replacement protocol. Clinicians may determine whether oral or intravenous replacement should be administered, as well as the dose and frequency of replacement. The PRICE-1 trial will only stipulate the threshold at which phosphate replacement may be initiated.

The restrictive protocol will stipulate phosphate replacement to commence at a threshold of 0.50 mmol/L, and the liberal protocol at 0.80 mmol/L. All other treatment will be at the discretion of the treating clinician.

During the first study period, the three participating ICUs will be randomised to either the restrictive or liberal phosphate replacement protocol. At the completion of the first study period (i.e., after three months), there will be a one-month washout period. For the second study period, the ICUs will crossover to the alternate phosphate replacement protocol i.e., if ICU-A used the restrictive protocol for the first study period, it will crossover to the liberal protocol for the second study period, and vice versa.

The use of the allocated protocol and adherence to the protocol will be monitored using electronic medical records.

Intervention code [1]

Treatment: Other

Comparator / control treatment

The restrictive protocol will stipulate phosphate replacement to commence at a threshold of 0.50 mmol/L, and the liberal protocol at 0.80 mmol/L.

The liberal phosphate replacement protocol, which is modeled current practices in the participating ICUs, will serve as the comparator.

Control group

Active

Outcomes

Primary outcome [1]

Difference in total phosphate replacement (measured in mmol and including both oral and intravenous replacement) between the restrictive and liberal phosphate replacement groups.

This is a composite outcome comprising oral and intravenous phosphate. This data will be collected by extraction from the electronic medical record using pre-tested Structure Query Language (SQL) scripts.

Timepoint [1]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [1]

Quantities of intravenous phosphate replaced

Timepoint [1]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [2]

ICU length of stay

Timepoint [2]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [3]

ICU mortality

Timepoint [3]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [4]

Acute kidney injury (defined as increase in serum creatinine to greater than or equal to 1.5 times baseline serum creatinine determined by hospital medical record review)

Timepoint [4]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [5]

Symptomatic cardiac rhythm disturbance determined by electronic medical record review

Timepoint [5]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [6]

Mechanical ventilation hours determined by electronic medical record review

Timepoint [6]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [7]

Tracheal reintubation determined by electronic medical record review

Timepoint [7]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [8]

Tracheostomy insertion determined by electronic medical record review

Timepoint [8]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [9]

Quantity of intravenous phosphate replaced determined by electronic medical record review

Timepoint [9]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [10]

Hospital mortality

Timepoint [10]

Duration of hospital admission as recorded in the hospital medical record

Secondary outcome [11]

Proportion of patients receiving phosphate replacement determined by electronic medical record review

Timepoint [11]

Duration of ICU admission as recorded in the electronic medical record

Secondary outcome [12]

Acceptability of phosphate replacement protocols among doctors and nurses working in participating ICUs determined by surveys conducted during the last week of each of the two study periods. A custom-designed survey, pilot-tested within the investigators' group, was developed for this purpose.

Timepoint [12]

Last week of recruitment into each of the two study periods

Secondary outcome [13]

Effective database-integration (defined as ability to extract 100% of patient data required for the trial through automated data extraction without the need for manual data collection). To calculate this percentage, a denominator and numerator are required. The total number of data points required, which form the denominator, are pre-specified. The numerator consists of data points which are able to be extracted by the automated data extraction process.

Timepoint [13]

At completion of trial

Secondary outcome [14]

Feasibility. This is a composite outcome incorporating both acceptability of the phosphate replacement protocols ((assessed using study-specific surveys during the last week of recruitment in each of the two study periods) and effectiveness of database-integration (by calculating the percentage of data which is extracted using the automated data extraction process) (as defined in secondary outcomes 12 and 13)

Timepoint [14]

At completion of trial

Eligibility

Key inclusion criteria

All patients admitted to the participating ICUs during the study period

Minimum age

18 Years

Maximum age

No limit

Sex

Both males and females

Can healthy volunteers participate?

Key exclusion criteria

1) Patients admitted solely for provision of palliative care or awaiting organ donation
2) Patients who have already been included in the PRICE-1 trial (i.e., only the first ICU admission for each patient during the trial will be eligible for inclusion in the trial)

Study design

Purpose of the study

Treatment

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

Allocation will not be concealed.

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Randomisation will be performed using computer-generated tables to allocate sites to the restrictive or liberal phosphate replacement protocol.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Crossover

Other design features

Cluster crossover trial

Phase

Not Applicable

Type of endpoint/s

Safety/efficacy

Statistical methods / analysis

Continuous data will be assessed for normality and presented as either mean or standard deviation (SD) or median and interquartile range (IQR). Categorical data will be presented as numbers and proportions. The primary outcome, difference in phosphate replacement between the two groups will be compared using (depending on normality) either an equality of medians or student t-test with appropriate adjustment for clustering. Among the other feasibility outcomes, protocol compliance will be assessed based on separation of daily serum phosphate concentrations. Acceptability of the two phosphate replacement protocols will be assessed using a short survey of ICU clinicians (doctors, nurses and pharmacists) at participating sites. The proportion of ICU patients receiving any phosphate replacement during their ICU admission will be compared using a Pearson chi-squared test. The database integration outcome will be assessed descriptively. Formal significance testing will only be performed for the primary outcome and for the difference in proportion of patients receiving any phosphate replacement. A p-value of <0.05 will be considered significant. The clinical outcomes will be assessed using appropriate methods adjusting for clustering and will be presented as odds ratio or mean difference with 95% confidence intervals without p-vales.

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

1/11/2022

Actual

Date of last participant enrolment

Anticipated

1/09/2023

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

1700

Accrual to date

Final

Recruitment in Australia

Recruitment state(s)

QLD

Recruitment hospital [1]

Caboolture Hospital - Caboolture

Recruitment hospital [2]

Redcliffe Hospital - Redcliffe

Recruitment hospital [3]

Royal Brisbane & Womens Hospital - Herston

Recruitment postcode(s) [1]

4510 - Caboolture

Recruitment postcode(s) [2]

4020 - Redcliffe

Recruitment postcode(s) [3]

4029 - Herston

Funding & Sponsors

Funding source category [1]

Other

Name [1]

Metro North Hospital and Health Services

Address [1]

Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029

Country [1]

Australia

Primary sponsor type

Other Collaborative groups

Name

The PRICE-1 Trial Investigators

Address

Metro North Hospital and Health Services
Royal Brisbane and Women's Hospital
Butterfield St
Herston QLD 4029

Country

Australia

Secondary sponsor category [1]

None

Name [1]

Address [1]

Country [1]

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Metro South Human Research Ethics Committee

Ethics committee address [1]

Human Research Ethics Office
Princess Alexandra Hospital
199 Ipswich Road
WOOLLOONGABBA, QLD, 4102

Ethics committee country [1]

Australia

Date submitted for ethics approval [1]

03/08/2022

Approval date [1]

Ethics approval number [1]

Summary

Brief summary

Derangements of serum phosphate concentrations, specifically hypophosphataemia, are common among ICU patients and our previous work has suggested this may be associated with worse clinical outcomes, including higher mortality and morbidity. Although replacement of phosphate through both intravenous and enteral routes is common in ICUs, the optimum threshold of serum phosphate at which to commence active replacement in critically ill patients is currently unknown, and the benefits have never been confirmed with an RCT. Resultantly, there are no consensus guidelines on phosphate replacement in ICU, with individual ICUs and clinicians self determining thresholds at which to replace phosphate. Such treatment comes at significant cost and there are potential adverse outcomes associated with phosphate replacement including hypocalcaemia (potentially precipitous and life-threatening), nausea, vomiting, diarrhoea and hypotension. Thus, ICU clinicians are left with substantial uncertainty about the optimal threshold at which to replace phosphate.

Therefore, a clinical and ethical imperative exists to conduct a high-quality, investigator initiated, RCT to inform clinical practice with regards to phosphate replacement and its impacts on patient centred outcomes in critically ill patients.

The PRICE-1 RCT will compare the use of a restrictive phosphate replacement protocol against a liberal phosphate replacement protocol for the management of serum phosphate levels in critically ill patients. The liberal protocol will start replacing phosphate when the serum concentration is below 0.80 mmol/L, whereas the restrictive protocol will start replacement when the serum phosphate concentration is below 0.50 mmol/L. The choice of oral versus intravenous phosphate administration is determined by the functioning of the patient's gastrointestinal tract. All other aspects of patient care will be determined by the treating clinicians as is appropriate for the condition/s with which the patients are admitted to the Intensive Care Unit.  

We hypothesise that use of a restrictive phosphate replacement protocol, compared to a liberal protocol, will result in reduced amount of phosphate replacement administered to critically ill patients in the Intensive Care Unit. Additionally, we hypothesise that the conduct of an electronic database-integrated cluster randomised trial will be feasible.

Trial website

Trial related presentations / publications

Public notes

Nil

Contacts

Principal investigator

Name

Dr Mahesh Ramanan

Address

ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510

Country

Australia

Phone

+61 07 5316 5956

Fax

mahesh.ramanan@health.qld.gov.au

Contact person for public queries

Name

Mahesh Ramanan

Address

ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510

Country

Australia

Phone

+61 07 5316 5956

Fax

mahesh.ramanan@health.qld.gov.au

Contact person for scientific queries

Name

Mahesh Ramanan

Address

ICU
Caboolture Hospital
McKean St, Caboolture QLD 4510

Country

Australia

Phone

+61 07 5316 5956

Fax

mahesh.ramanan@health.qld.gov.au

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

No/undecided IPD sharing reason/comment

IPD sharing was not part of the ethics approval

What supporting documents are/will be available?

No Supporting Document Provided

Results publications and other study-related documents

Documents added manually

No documents have been uploaded by study researchers.

Documents added automatically

No additional documents have been identified.

Trial Review

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